Unveiling cell phenotypes in lung vascular remodeling

Abstract

PULMONARY VASCULAR REMODELING is a hallmark of most forms of pulmonary hypertension (PH), both primary and secondary. This remodeling takes the form of concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by increased numbers of vascular smooth muscle cells (SMCs) as well as by hypertrophy of individual SMCs (25). In human PH, characteristic plexiform lesions develop, and there is increasing discussion of neovasculogenesis and angiogenesis during remodeling. The vascular remodeling is associated with hypoxia- or inflammationinduced production of growth factors, angiogenic factors, inflammatory mediators, and vasoconstrictors. For decades, investigators have attempted to dissect the mechanisms behind this lung-specific vascular remodeling, investigating a wide range of environmental stimuli, hemodynamic events, biochemical and molecular signaling pathways, and extracellular matrix changes. Recently, investigators have begun looking in greater detail at the heterogeneity of cells in lung vascular walls under normal and pathological remodeling conditions (14, 26). Initially, it was recognized that even within a single region, endothelial cells differ and may have highly distinct characteristics and functions. Now there is increasing interest in and evidence for the existence of diverse cell types within the media of remodeling lung vessels. Emerging evidence suggests that endogenous or circulating inflammatory and/or progenitor cells contribute significantly to the remodeling process (9, 22). The term “circulating inflammatory/progenitor cells” characterizes a wide variety of cell populations that differ with respect to their structural characteristics, expression of marker molecules, and biological functions. These cells include macrophages and other inflammatory cells, mononuclear cells, stem cells, endothelial progenitor cells, fibrocytes, and myofibroblasts. The nature of these cells, their relative importance, and their derivation and source continue to be unclear and highly controversial. The phenotype of these cells may change during the remodeling process or vary with the specific initiating pathophysiology or type of PH. Thus, it is important to define the phenotype of cells in the vascular media and the roles of the cells in the normal and diseased pulmonary vasculature. The exact source of the cells is also important to know because it may determine cell phenotype and targets for